Transactions of the Royal Society of Tropical Medicine and Hygiene (2007) 101, 517—522

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Reaction time in patients with HIV/AIDS andcorrelation with CD4 count: a case—control study

A.O. Ogunrina,∗, F.E. Odiasea, A. Ogunniyib

a Neurology Unit, Department of Medicine, University of Benin Teaching Hospital, Benin City, Nigeriab Neurology Unit, Department of Medicine, University College Hospital, Ibadan, Nigeria

Received 6 April 2006; received in revised form 21 October 2006; accepted 23 October 2006Available online 23 January 2007

KEYWORDSHIV;AIDS;CD4 lymphocytecount;Psychomotorperformance;Reaction time;Nigeria

Summary There are conflicting reports on the presence of neurocognitive dysfunction duringthe initial, medically asymptomatic stage of HIV infection. This study aimed to assess the psy-chomotor speed and attention ability of antiretroviral treatment-naıve Nigerian Africans withHIV/AIDS and the impact of CD4 levels on their cognitive performance. Two hundred and eighty-eight randomly selected age-, sex- and level of education-matched subjects participated,comprising 96 HIV-positive asymptomatic and 96 HIV-positive symptomatic patients and 96 HIV-negative controls. The simple reaction and binary choice reaction time tasks were used forcognitive assessment. The binary choice reaction time indicated that the HIV-positive patientshad impaired attention ability and significant psychomotor slowing compared with the controls(P < 0.05), but psychomotor slowing was obvious among the symptomatic HIV-positive patientsonly using the simple reaction time tasks. Significant psychomotor retardation was observedin HIV-positive patients with CD4 levels of 200—499 cells/mm3 (P = 0.02) and <200 cells/mm3

(P < 0.001), and impaired ability for sustained attention was present irrespective of the CD4

level (P < 0.001). We conclude that psychomotor retardation and impaired attention are sig-nificantly worse in HIV-positive subjects compared with controls and are adversely affected bydecreasing CD4 levels. The sensitivity of the neuropsychological tool used can affect the degreeof impairment measured.© 2006 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rightsreserved.

1

Chave been reported during advanced stages of the disease

∗ Corresponding author. Present address: Department of Medicine,

PMB 1154, College of Medical Sciences, University of Benin, BeninCity, Nigeria. Tel.: +234 80 2334 4044; fax: +234 52 600 672.

E-mail addresses: bfunmi@uniben.edu,bunmifunmi@hotmail.com (A.O. Ogunrin).

a2la

0035-9203/$ — see front matter © 2006 Royal Society of Tropical Medicindoi:10.1016/j.trstmh.2006.10.002

. Introduction

ognitive symptoms specifically related to HIV infection

nd with cases of severe immunosuppression (Ferrando,000; Heaton et al., 1995; Selnes, 2005). The neuropsycho-ogical deficits reported in HIV infection include decreasedttention and concentration, psychomotor slowing, reduced

e and Hygiene. Published by Elsevier Ltd. All rights reserved.

5 A.O. Ogunrin et al.

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Table 1 Clinical symptoms of 96 HIV-positive symptomaticpatients

Symptom Frequency (%)

Unexplained fevera 92 (96)Weight lossb 96 (100)Diarrhoeac 80 (83)Skin rash 64 (67)a Fever was defined as a body temperature >37.20 ◦C presentfor >8 weeks.b Weight loss was defined as loss of ≥10% of previous bodyweight.

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peed of information processing, executive dysfunctionincluding abstraction, divided attention, shifting cognitiveets, response inhibition) and verbal memory impairmentparticularly retrieval of stored information) (Heaton et al.,995; Sacktor et al., 1995; Selnes, 2005). The neuropsy-hological deficits in HIV infection resemble those seen inther subcortical—frontal disorders such as Parkinson’s dis-ase (Selnes, 2005).

There is evidence to show that HIV damages the brainirectly through the elaboration of virally mediated tox-ns (gp120, tat and Nef) and indirectly through hostoxins (quinolinic acid, TNF-�, platelet activating factor,itric oxide, neopterins and peroxynitrite) (Epstein andendelman, 1993; Nath, 2002). These neurotoxic effectsromote neurodegeneration by synergism of HIV productsith endogenous excitotoxins as well as interference of HIVith the effects of growth factors that are essential for neu-

onal survival and maintenance (Masliah et al., 1996). Theonsequences include neurocognitive dysfunctions, whichanifest in their mild form as minor cognitive motor disorder

MCMD) and grossly as HIV-associated dementia (HAD).With the increasing incidence of HIV/AIDS in sub-Saharan

frica, where it is responsible for over 2 million deathsnd where there are 15 000 new cases annually (De Cocknd Weiss, 2000; UNAIDS, 2004), the cognitive impairmentsssociated with HIV and the consequent reduced functionalapacity of affected individuals will significantly affectuality of life and increase mortality. We assessed the psy-homotor speed and attention ability of Nigerian Africansith HIV/AIDS and correlated their performances with theirD4 counts.

. Methods

.1. Study population

total of 192 HIV-positive subjects were randomly recruitedor this study over a period of 6 months (January—June004) from the HIV/AIDS clinics of the University Teachingospital, Benin City, Nigeria. The subjects comprised 96IV-positive asymptomatic and 96 HIV-positive symptomaticatients. In addition, 96 seronegative volunteers wereandomly selected from the outpatient clinics, antenatallinics and among hospital staff members as controls. ELISAas used to detect HIV antibodies and to diagnose HIV

nfection, and CD4 levels were determined for all subjectsy automated flow cytometry (CyFlowTM; Partec GmbH,unster, Germany) and double-checked with a manualD4 kit (Coulter®; Partec GmbH, Munster, Germany). Allubjects were matched for age, sex and level of education.nformed consent was obtained from the patients andontrols, and approval to undertake the study was grantedy the Hospital Ethics Committee.

All subjects were interviewed using a basic question-aire by one of the authors (F.E.O.) to obtain demographicariables. The inclusion criteria for patients were HIV

eropositivity in asymptomatic and symptomatic individu-ls who were ≥18 years of age. Exclusion criteria includedatients who were <18 years of age, patients already onntiretroviral therapy, patients with active opportunisticnfections, patients with co-morbidity (diabetes mellitus,

bew(i

c Diarrhoea was defined as increased frequency of bowelmotions and/or change in consistency (i.e. loose or waterymotions).

ypertension, epilepsy and associated intracranial disor-ers, e.g. brain tumour and other metabolic diseases),hose with inconclusive diagnosis, major axis 1 psychi-tric illness, presence of clinical signs of cardiac failure,lcohol intake >120 g/week or 13 units/week, history of pre-ious head injury with loss of consciousness and patientsn anticholinergic medications. The clinical symptoms ofhe HIV-positive symptomatic patients are outlined inable 1.

The HIV-positive patients were categorised into threeroups according to the CD4 counts, based on the CDC clin-cal case definition criteria (CDC, 1992).

.2. Cognitive assessment

he simple reaction time (comprising auditory and visualasks) and binary choice tasks, which are components ofhe computer-assisted neuropsychological test battery Ironsychology (‘FePsy’) (Moerland et al., 1986), were used forognitive assessment. The binary choice test involves theisplay of either a red or a green half square-inch block in aandom sequence in either the left or right half of a screen.he testee is asked to push one of two buttons on either sidef a keyboard, corresponding to the position of the colouredlock on the screen. The test is ‘self-paced’ and continu-us, which implies that a response is immediately followedy substitution of another block in either the same or in thepposite position. After an initial practice of 10 stimuli, 60timuli are presented.

The results show accuracy and speed (in ms) of responses.valuation is carried out in the context of speed of informa-ion processing (psychomotor speed) and attention.

In the auditory version of the simple reaction task, theestee was asked to react as quickly as possible to soundtimuli of 800 Hz generated by the computer.

For the visual version, the testee reacts as quickly asossible to a white square in the middle of the computercreen. In both versions, the interstimulus interval is ran-omly varied from 2.5 s to 4 s. Details of this procedure haveeen described previously (Ogunrin et al., 2000; Unuigbe

t al., 2004). Test presentation and response registrationere controlled by a microcomputer, but one of the authors

A.O.O.) was always present to adjust instructions to thendividual performance level of the patients. The cognitive

Reaction time in patients with HIV/AIDS and correlation with CD4 count 519

Table 2 Demographic information on HIV-positive patients and controls

Characteristic Controls (n = 96), n (%) HIV-positive

Asymptomatic (n = 96), n (%) Symptomatic (n = 96), n (%)

SexMale 48 (50) 48 (50) 48 (50)Female 48 (50) 48 (50) 48 (50)

Age (years)20—29 40 (42) 43 (45) 40 (42)30—39 34 (35) 37 (39) 34 (35)40—49 21 (22) 16 (17) 21 (22)≥50 1 (1) 0 1 (1)

Level of educationPrimarya 48 (50) 48 (50) 48 (50)Secondaryb 36 (38) 36 (38) 36 (38)Tertiaryc 12 (13) 12 (13) 12 (13)

darytions

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a Duration of schooling ≤6 years with no post-primary education.b Duration of schooling >6 years but <12 years, with no post-seconc Duration of schooling ≥12 years (university or equivalent institu

assessment was blinded, as the author (A.O.O.) was notaware of the patient’s HIV status.

The average binary choice reaction time (mean ± SD)for normal Nigerians in the age range 18—45 years is422 ± 92.3 ms (sensitivity 0.85 ± 0.14 ms). The average nor-mal auditory reaction time is 296.2 ms and 284.6 ms forthe dominant and non-dominant hand, respectively, and theaverage visual reaction time is 266.9 ms and 272.8 ms for thedominant and non-dominant hand, respectively.

2.3. Statistical analysis

Statistical analysis of the data was performed using Epi Info2000 (CDC, Atlanta, GA, USA), utilising two-way ANOVA tocompare the means of the cognitive performances of thethree groups of subjects, odds ratios to express strength ofassociation and �2 for trend to determine the impact of CD4

HNwpt

Table 3 Mean cognitive scoresa of HIV-positive patients and cont

Controls (n = 96) AsymptomaticHIV-positive (n =

Mean CD4 count (/mm3) 682 ± 44 284 ± 62Mean age (years) 32.94 ± 8.0 31.47 ± 6.7

Binary choice reactionTime taken (ms) 432.78 ± 170.37 557.05 ± 126.30Sensitivity (% correct) 95.06 ± 5.19 90.04 ± 4.47

Simple reaction time (ms)Auditory

Dominant 488.79 ± 11.34 494.58 ± 14.27Non-dominant 481.58 ± 9.46 479.76 ± 11.24

VisualDominant 581.29 ± 16.12 593.16 ± 14.28Non-dominant 574.62 ± 10.16 582.98 ± 13.24

a Expressed as mean ± SD.b Level of significance (P < 0.05) compared independently with the con

education.).

n cognitive performances. The HIV-positive groups wereeparately matched with the control group.

. Results

ll 288 subjects completed the study and their demographicnformation is outlined in Table 2.

The mean cognitive scores of all the study subjectsre summarised in Table 3. The binary choice reactionime revealed significant differences in the time takenpsychomotor determinant) to perform the tasks (P < 0.05)nd the sensitivity (attention/concentration ability) of the

IV-positive patients compared with the controls (P < 0.05).o difference was observed in the simple reaction taskshen the performances of the asymptomatic HIV-positiveatients were compared with the controls (P > 0.05), buthe symptomatic HIV-positive patients performed poorly

rols

96)P-valueb Symptomatic

HIV-positive (n = 96)P-valueb

<0.001 142 ± 36 <0.0010.21 33.56 ± 7.1 0.33

<0.001 665.17 ± 128.27 <0.0010.01 85.13 ± 6.21 <0.001

0.38 668.75 ± 16.24 <0.010.13 594.21 ± 21.18 <0.01

0.43 662.15 ± 11.36 <0.010.27 634.42 ± 14.69 <0.01

trol group.

520

Tabl

e4

Corr

elat

ion

ofCD

4co

unts

wit

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nary

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acti

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Sens

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(95%

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Cont

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(n=

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532.

78±

170.

3721

.495

.06

±5.

1918

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CD4

coun

t(/

mm

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(n=

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>500

553.

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173.

2427

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411.

40(0

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2.70

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8950

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4.52

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17±

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16.6

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A.O. Ogunrin et al.

significantly prolonged reaction time) compared with theontrols (P < 0.01).

There was progressive deterioration in the psychomo-or speed of the HIV-positive patients as the CD4 countecreased (Table 4). There was no significant difference inhe performance of patients with CD4 counts >500 cells/mm3

ompared with controls, although 27.6% of them had a pro-onged reaction time. However, for patients with counts of00—499 cells/mm3 (P = 0.02) and <200 cells/mm3 (P < 0.001)he difference became significant, with 38.5% and 82.7%f these patients having prolonged reaction time, respec-ively (Table 4). A similar trend was observed with theimple reaction tasks, although the differences betweenhe controls and HIV-positive patients with CD4 levels500 cells/mm3 and 200—499 cells/mm3 were not significantP > 0.05) (Table 5).

As the CD4 count decreased, the HIV-positive patients hadncreasingly reduced sensitivity compared with the controlsP < 0.001 for all counts) (Table 4).

. Discussion

mpairments in psychomotor speed have been reported inIV/AIDS patients, especially when computerised neuropsy-hological tools are used because of their capability toetect subtle cognitive decline (Miller et al., 1991; Perdicesnd Cooper, 1989; Wilkie et al., 1990).

There have been conflicting reports on the neurocogni-ive performances of asymptomatic HIV-positive individualsSelnes et al., 1990, 1992; Wilkie et al., 1990) and thisas been linked to differences in the sensitivity of variouseuropsychological tests (White et al., 1995). Our studyndicates that the sensitivity of the neuropsychologicalest used plays a significant role in defining the degreef cognitive impairment in patients with HIV/AIDS, asignificant impairments were noted only when the binaryhoice reaction time was used.

It has not yet been agreed exactly how much increasedisk of neuropsychological impairment patients with AIDSxperience. We observed that the risks of psychomotoretardation and attention deficit significantly increased withrogressive decline in CD4 counts. This proved the impactf progressive immunosuppression in HIV/AIDS on atten-ion/concentration and psychomotor speed. Our observationorroborates the findings of Bacellar et al. (1994) anderdices and Cooper (1989). However, cognitive impair-ent was rarely encountered in patients with CD4 levels

500 cells/mm3. It is important to recognise that the risk ofeveloping HAD may be variable even within a range of CD4ounts, as some patients will never develop HAD or may shownly MCMD despite advanced disease, whilst in others cogni-ive impairment may be the predominant illness. Numerousross-sectional and longitudinal studies have proved theenefits of highly active antiretroviral therapy (HAART)egimens in the management of HAD and neurocognitive

mpairment, with the most consistent improvements seen insychomotor processing speed (Ferrando et al., 2003; Tozzit al., 1999). Marra et al. (2003) reported that HAART reg-mens containing zidovudine and indinavir were superior tother regimens in improving neurocognitive performance.

Reaction time in patients with HIV/AIDS and correlation with CD

Tabl

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Corr

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wit

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Tim

eta

ken

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ith

prol

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dti

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488.

79±

11.3

422

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4618

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4co

unt

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(n=

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491.

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518

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590.

78(0

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1.56

)46

8.57

±11

.23

21.1

0.86

1.14

(0.5

6—2.

32)

200—

499

498.

37±

13.2

430

0.33

1.46

(0.7

6—2.

78)

477.

21±

9.21

31.6

0.66

1.97

(1.0

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<200

674.

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173

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(4.9

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588.

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678

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3)

Visu

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1.29

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574.

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4co

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(n=

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>500

593.

42±

11.2

320

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581.

32(0

.64—

2.73

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9.69

±9.

8325

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731.

19(0

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0—49

958

8.24

±10

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(0.5

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57)

583.

44±

11.4

321

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001.

06(0

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0065

9.17

±17

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74.5

<0.0

0115

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.39—

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6)64

3.11

±12

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61.2

<0.0

015.

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odds

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4 count 521

The national policy on the management of HIV/AIDS inigeria, where patients are not commenced on HAART untilheir CD4 counts are <250 cells/mm3, needs revision tollow for prompt and early management of HIV-associatedeurocognitive impairment. Furthermore, the regimen ofidovudine, nevirapine and stavudine, which is employedn the management of these patients, needs to be modifiedo allow the inclusion of indinavir, a protease inhibitor thateadily crosses the blood—brain barrier.

Neuropsychological evaluation is mandatory for patientsith HIV/AIDS. The HIV Dementia Scale of Power et al.

1995) is a rapid screening test suitable for use in ruralnd suburban health institutions for this purpose. It doesot require special training to understand its application.his test assesses psychomotor processing speed, verbalemory, constructional ability and executive function

response inhibition, set shifting). Its utility for assessingild HIV-associated cognitive deficits is, however, limited

Smith et al., 2003). Thus, there is a need for studies witharger sample sizes that evaluate the impact of neurocog-itive disturbance and the effect of HAART intervention onhe quality of life for patients with HIV/AIDS in Africa.

onflicts of interest statementhe authors have no conflicts of interest concerning the workeported in this paper.

uthors’ contributions

OO and AO designed the study protocol; FEO carried outhe recruitment, and the clinical and interview assessmentf patients and controls; AOO conducted the neurocognitivessessment; AOO carried out the analysis and interpretationf the data; AO, AOO and FEO drafted the manuscript. Alluthors read and approved the final manuscript. AOO andEO are guarantors of the paper.

cknowledgements

he authors express their gratitude to the nurses and lab-ratory scientists in the HIV/AIDS clinics of the Universityeaching Hospital, Benin City, Nigeria, for their co-operationuring the study period.

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